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For the
first time researchers have shown that a commonly used anesthetic can produce
changes associated with Alzheimer’s disease in the brains of living mammals,
confirming previous laboratory studies.In their Annals of Neurology report, which has received early online
release, a team of Massachusetts General Hospital (MGH) investigators shows how
administration of the gas isoflurane can lead to generation of the toxic
amyloid-beta (A-beta) protein in the brains of mice.

“These are
the first in vivo results indicating that isoflurane can set off a
time-dependent cascade inducing apoptosis [cell death] and enhanced levels of
the Alzheimer’s-associated proteins BACE and A-beta,” says Zhongcong Xie, MD,
PhD, of the MassGeneral Institute for Neurodegenerative Disease (MGH-MIND) and the
MGH Department of Anesthesia and Critical Care, the study's lead and
corresponding author. “This work needs to be confirmed in human studies, but it’s
looking like isoflurane may not be the best anesthesia to use for patients who
already have higher A-beta levels, such as the elderly and Alzheimer’s patients.”

Alzheimer's
disease is characterized by deposition of A-beta plaques within the brain.The A-beta protein is formed when the larger
amyloid precursor protein (APP) is clipped by two enzymes – beta-secretase,
also known as BACE, and gamma-secretase – to release the A-beta fragment.Normal processing of APP by an enzyme called
alpha-secretase produces an alternative, non-toxic protein.

Several
studies have suggested that surgery and general anesthesia may increase the
risk of developing Alzheimer's disease, and it is well known that a small but
significant number of surgical patients experience a transient form of dementia
in the postoperative period.Last year
the MGH team showed that applying isoflurane to cultured neural cells increased
activation of the cell-death protein caspase and raised levels of BACE and
gamma-secretase as part of a pathway leading to the generation of A-beta.The current study was designed to see if the
same process takes place in mice.

Neurologically
normal mice received isoflurane for two hours at doses comparable to what would
be administered to human patients.Their
brains were examined 2, 6, 12 and 24 hours after they received the anesthesia
and compared with the brains of control mice.Results at 6 hours showed that caspase levels were elevated and BACE had
modestly increased in mice that received isoflurane.At 12 hours moderate caspase activation
persisted, and BACE levels were even higher in the treated mice; and at 24
hours BACE levels were more than four times higher than in controls, and A-beta
levels had also risen, while caspase activation had fallen off.

Another
group of mice had been treated for seven days with the drug clioquinol before
the two-hour isoflurane administration.Laboratory studies have found that clioquinol inhibits the aggregation
of A-beta into neurotoxic deposits, and a clioquinol derivative is currently in
clinical trials as an Alzheimer’s treatment drug.Six hours after they received isoflurane,
caspase levels in the clioquinol-treated mice were significantly less than in
other animals that had received the anesthetic, suggesting both that A-beta
aggregation contributes to a vicious cycle of further cell death –echoing a finding from the team’s 2007 study
– and that a drug like clioquinol might block isoflurane’s neurotoxic effects.

“This study
cannot tell us about the long-term effects of isoflurane administration; that’s
something we will examine in future investigations,” notes Xie, who is an
assistant professor of Anesthesia at Harvard Medical School (HMS) and director
of the Geriatric Anesthesia Research Unit in the MGH Department of Anesthesia
and Critical Care.

“Until we
can directly assess the impact of isoflurane on biomarkers like A-beta levels
in the plasma or cerebrospinal fluid of human patients, we cannot conclusively
determine its role in increasing the risk for Alzheimer’s or postoperative
dementia,” adds Rudolph Tanzi, PhD, director of the MGH-MIND Genetics and Aging
Research Unit, senior author of the study, and the Joseph P. and Rose F.
Kennedy Professor of Neurology at HMS.

The study
was supported by grants from the National Institutes of Health, the American
Geriatrics Society, the Alzheimer’s Association, HarvardUniversity
and the Cure Alzheimer’s Fund. Tanzi is a co-founder, consultant and holds
equity in Prana Biotechnology, Ltd, the company conducting a clinical trial of
clioquinol derivative PBT2.Xie is a
consultant of Baxer Healthcare, the company that produces isoflurane. Neither
company supported or had any other connection with the current study.

Massachusetts GeneralHospital,
established in 1811, is the original and largest teaching hospital of HarvardMedicalSchool.
The MGH conducts the largest hospital-based research program in the United States,
with an annual research budget of more than $500 million and major research
centers in AIDS, cardiovascular research, cancer, computational and integrative
biology, cutaneous biology, human genetics, medical imaging, neurodegenerative
disorders, regenerative medicine, systems biology, transplantation biology and
photomedicine.